Combinations comprising metap2 inhibitors for the treatment of cancer

Abstract

The present disclosure provides pharmaceutical combinations comprising MetAP2 inhibitors for the treatment of cancer.

What is claimed is: 
     
         1 . A combination comprising at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and eribulin, or a pharmaceutically acceptable salt thereof, for use in treating a cancer in a subject,
 wherein the MetAP2 inhibitor is:   
       
         
           
           
               
               
           
         
          or a pharmaceutically acceptable salt thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:1. 
       
     
     
         2 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of eribulin, or a pharmaceutically acceptable salt thereof,
 wherein the MetAP2 inhibitor is:   
       
         
           
           
               
               
           
         
          or a pharmaceutically acceptable salt thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:1. 
       
     
     
         3 . The combination for use or method of  any one of the preceding claims , wherein the at least one MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and the eribulin, or pharmaceutically acceptable salt thereof, are administered concurrently or in temporal proximity. 
     
     
         4 . The combination for use or method of  any one of the preceding claims , wherein the eribulin is eribulin mesylate. 
     
     
         5 . The combination for use or method of  any one of the preceding claims , wherein the eribulin is administered/for administration to the subject in an amount of:
 i) about 1.4 mg/m 2 ;   ii) about 1.1 mg/m 2 ; or   iii) about 0.7 mg/m 2 , and   wherein the MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, is administered/for administration to the subject in an amount of:   i) about 49 mg/m 2 ;   ii) about 36 mg/m 2 ; or   iii) about 65 mg/m 2 ; or   iv) about 27 mg/m 2 .   
     
     
         6 . The combination for use or method of  any one of the preceding claims , wherein the MetAP2 inhibitor is administered/for administration:
 i) once every 14 days (Q14D);   ii) once every 7 days (Q7D); or   iii) once every 21 days (Q21D).   
     
     
         7 . The combination for use or method of  any one of the preceding claims , wherein the eribulin is administered/for administration on day 1 and one day between days 5 and 11 (inclusive) of a 21-day cycle, preferably wherein the eribulin or eribulin mesylate is administered/for administration on day 1 and day 8 of a 21-day cycle. 
     
     
         8 . The combination for use or method of  any one of the preceding claims , wherein the eribulin and the MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, is administered/for administration to the subject in a first 21-day cycle, followed by a second 21-day cycle,
 wherein the first 21-day cycle comprises:   i) administering the MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, on days 1 and 15 of the first 21-day cycle; and   ii) administering the eribulin on day 1 and one day between days 5 and 11 (inclusive), preferably day 8, of the first 21-day cycle;   wherein the second 21-day cycle comprises:   i) administering the MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, on day 8 of the second 21-day cycle; and   ii) administering the eribulin on day 1 and one day between days 5 and 11 (inclusive), preferably day 8, of the second 21-day cycle.   
     
     
         9 . The combination for use or method of  any one of the preceding claims , wherein the eribulin and the MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, is administered/for administration to the subject in 21-day cycle, wherein the 21-day cycle comprises:
 i) administering the MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, on days 1 and 8 of the 21-day cycle; and   ii) administering the eribulin on days 1 and 8 of the 21-day cycle;   or   i) administering the MetAP2 inhibitor once during the 21-day cycle; and   ii) administering the eribulin on days 1 and 8 of the 21-day cycle.   
     
     
         10 . The combination for use or method of  any one of the preceding claims , wherein the subject:
 i) has breast cancer, preferably wherein the breast cancer is triple-negative beast cancer, preferably wherein the triple-negative breast cancer is metastatic.   ii) has at least one of:
 a) a BMI of greater than or equal to about 30 kg/m 2 ; and 
 b) an HbA1c level of greater about 5.5%; and/or 
   iii) has previously received at least one line of treatment for the cancer.   
     
     
         11 . A combination comprising at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, fulvestrant, or a pharmaceutically acceptable salt thereof, and alpelisib, or a pharmaceutically acceptable salt thereof, for use in treating a cancer in a subject,
 wherein the MetAP2 inhibitor is:   
       
         
           
           
               
               
           
         
          wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:1. 
       
     
     
         12 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, at least one therapeutically effective amount of fulvestrant, or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of alpelisib, or a pharmaceutically acceptable salt thereof,
 wherein the MetAP2 inhibitor is:   
       
         
           
           
               
               
           
         
          wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:1. 
       
     
     
         13 . The combination for use or the method of  any one of the preceding claims , wherein the at least one MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, the alpelisib, or pharmaceutically acceptable salt thereof, and the fulvestrant, or pharmaceutically acceptable salt thereof, are administered concurrently or in temporal proximity. 
     
     
         14 . The combination for use or the method of  any one of the preceding claims ,
 wherein the alpelisib, or pharmaceutically acceptable salt thereof, is administered/for administration to the subject in an amount of:
 i) about 300 mg; 
 ii) about 250 mg; or 
 iii) about 200 mg, 
   wherein the fulvestrant, or pharmaceutically acceptable salt thereof, is administered/for administration to the subject in an amount of:
 i) about 500 mg; or 
 ii) about 250 mg; and 
   wherein the MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, is administered/for administration to the subject in an amount of:
 i) about 49 mg/m 2 ; 
 ii) about 36 mg/m 2 ; 
 iii) about 65 mg/m 2 ; or 
 iv) about 27 mg/m 2 . 
   
     
     
         15 . The combination for use or the method of  any one of the preceding claims ,
 wherein the MetAP2 inhibitor is administered/for administration once every 14 days (Q14D),   wherein the alpelisib inhibitor is administered/for administration once daily (QD), and   wherein the fulvestrant is administered/for administration once every 14 days (Q14D), preferably wherein following the third administration of fulvestrant, the fulvestrant is administered/for administration once every 28 days (Q28D).   
     
     
         16 . The combination for use or the method of  any one of the preceding claims , wherein the MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, the alpelisib, or pharmaceutically acceptable salt thereof, and fulvestrant, or pharmaceutically acceptable salt thereof, is administered/for administration to the subject in a first 28-day, followed by a second 21-day cycle,
 wherein the first 28-day cycle comprises:   i) administering the MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, on days 1 and 15 of the first 28-day cycle;   ii) administering the fulvestrant, or pharmaceutically acceptable salt thereof, on days 1 and 15 of the first 28-day cycle; and   iii) administering the alpelisib, or pharmaceutically acceptable salt thereof, on each of days 15-28 of the first 28-day cycle;   wherein the second 21-day cycle comprises:   i) administering the MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, on days 1 and 15 of the second 28-day cycle; and   ii) administering the fulvestrant, or pharmaceutically acceptable salt thereof, on day 1 of the second 28-day cycle; and   iii) administering the alpelisib, or pharmaceutically acceptable salt thereof, on each of days 1-28 of the second 28-day cycle.   
     
     
         17 . A combination comprising at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and inavolisib, or a pharmaceutically acceptable salt thereof, for use in treating a cancer in a subject,
 wherein the MetAP2 inhibitor is:   
       
         
           
           
               
               
           
         
          wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:1. 
       
     
     
         18 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of inavolisib, or a pharmaceutically acceptable salt thereof,
 wherein the MetAP2 inhibitor is:   
       
         
           
           
               
               
           
         
          wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:1. 
       
     
     
         19 . The combination for use or the method of  any one of the preceding claims ,
 wherein the inavolisib is administered/for administration to the subject in an amount of:
 i) about 3 mg; 
 ii) about 6 mg; 
 iii) about 9 mg; or 
 iv) about 12 mg; and 
   wherein the MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, is administered/for administration to the subject in an amount of:
 i) about 49 mg/m 2 ; 
 ii) about 36 mg/m 2 ; or 
 iii) about 65 mg/m 2 . 
   
     
     
         20 . The combination for use or the method of  any one of the preceding claims ,
 wherein the MetAP2 inhibitor is administered/for administration once every 4 days (Q4D); and   wherein the inavolisib is administered/for administration once daily.   
     
     
         21 . The combination for use or the method of  any one of the preceding claims , wherein the subject has breast cancer, preferably wherein the breast cancer is HR+HER2− breast cancer, preferably wherein the breast cancer is relapsed breast cancer. 
     
     
         22 . The combination for use or the method of  any one of the preceding claims , preferably wherein the breast cancer is
 i) characterized by progressive disease more than about 12 months from the completion of a neoadjuvant and/or adjuvant endocrine therapy;   ii) identified to be progressive while the subject is being treated or after the subject has been treated with at least one endocrine therapy in combination with at least one CDK4/6 inhibitor.   
     
     
         23 . The combination for use or the method of  any one of the preceding claims , wherein the subject
 i) has been previously treated with at least one endocrine therapy in combination with at least one CDK4/6 inhibitor, preferably wherein the subject has been treated with the at least one endocrine therapy in combination with the at least one CDK4/6 inhibitor for at least about 12 months;   ii) hast at least one PIK3CA mutation;   iii) is a postmenopausal woman; and/or   iv) has at least one of:
 a) HbA1c levels of about 5.5% to about 6.4% 
 b) fasting plasma glucose (FPG) level of greater than about 100 mg/dL (5.6 mmol/L) and less than about 140 mg/dL (7.7 mmol/L); 
 c) a body mass index (BMI) of greater than about 20 kg/m 2    
 d) a Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score of greater than about 1.8 
 e) a BMI of greater than or equal to about 30 kg/m 2 ; and 
 f) an HbA1c level of greater than about 5.5%. 
   
     
     
         24 . The combination for use or the method of  any one of the preceding claims , wherein the subject has at least one metabolic dysfunction, wherein the at least one metabolic dysfunction is excessive visceral adiposity, dyslipidemia, obesity (BMI≥30), elevated leptin levels, depressed adiponectin levels, high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, high fasting glucose, elevated HbA1c, or any combination thereof.